The present invention relates to a process for preparing a heteroaromatic compound having a heteroaromatic nucleus substituted with one or more ether groups.
Polythiophenes and polypyrroles have been studied extensively due to their interesting electrical and/or optical properties (see Handbook of Conducting Polymers, Eds. Skotheim, T. A.; Elsenbaumer, R. L.; Reynolds, J. R., Marcel Dekker, New York, 1998, 2nd edition). Within these classes of electroconductive polymers, poly(3,4-alkylenedioxythiophenes) and poly(3,4-alkylenedioxypyrroles) have particularly useful electrical and/or optical properties. Poly(3,4-ethylenedioxythiophene) [PEDOT] in association with the polyanion poly(styrene sulfonic acid) [PSS] is one of the most commercially successful conductive polymers in the world. It is being used in a wide variety of applications as described by L. Groenendaal et al. in 2000 in Advanced Materials, volume 12, pages 481-494.
Two routes for preparing the monomers from which poly(3,4-alkylenedioxythiophenes) and poly(3,4-alkylenedioxypyrroles) are prepared, 3,4-alkylenedioxythiophenes, such as 2,3-dihydro-thieno [3,4-b][1,4]dioxine [also known as 3,4-ethylenedioxythiophene (EDOT)], and 3,4-alkylenedioxypyrroles have been disclosed: via a double Williamsson synthesis [see Pei et al. in 1994 in Polymer, volume 35, pages 1347-1351, for thiophene derivatives, and J. R. Reynolds et al. in 2001 in Journal of Organic Chemistry, volume 66, pages 6873-6882, and A. Merz et al. in 1995 in Synthesis, pages 795-800, for pyrrole derivatives], via the alkylation procedure reported by Halfpenny et al. in 2001 in Journal Chemistry Society, Perkins Transaction I, pages 2595-2603 who modified the alkylation procedure reported by Dallacker and Mues in 1975 in Chemische Berichte, volume 108, page 576 by using 1,2-bromoethane instead of bromochloromethane, and via transetherification of 3,4-dimethoxythiophene (see Reynolds et al in 1999 in Advanced Materials, volume 11, pages 1379-1382).
The double Williamson route and the alkylation procedure suffers from the disadvantages that it mostly uses xcex1,xcfx89-dichloro- or xcex1,xcfx89-dibromo-alkanes, which with short chain alkanes such as ethane or propane are extremely toxic, for the ring closure and that substituted derivatives (at the 2-position of the dioxine ring) are, if obtainable, only obtainable in low to very low yields.
The transetherification route has the disadvantages of involving the difficult and expensive synthesis of 3,4-dimethoxy-derivatives (not commercially available) and the low yields for reactions involving secondary alcohol groups. Furthermore, it is not possible to use this reaction for the preparation of pyrrole derivatives.
There is therefore a need for an alternative process for preparing 3,4-alkylenedioxythiophenes and 3,4-alkylenedioxypyrroles avoiding the above-mentioned problems.
It is therefore an aspect of the present invention to provide a process for preparing 3,4-alkylenedioxythiophenes and 3,4-alkylenedioxypyrroles in high yields, avoiding expensive and toxic intermediates.
Further aspects and advantages of the invention will become apparent from the description hereinafter.
It has been surprisingly found that the Mitsunobu reaction can be used to prepare a heteroaromatic compound having a heteroaromatic nucleus substituted with one or more ether groups at xcex1- or xcex2-positions with respect to a heteroatom of the heteroaromatic nucleus, whereas the Mitsunobu reaction is typically used for condensing alcohols with an acidic compound (Hxe2x80x94Nu) such as oxygen nucleophiles for example carboxylic acids and phenols; nitrogen nucleophiles for example imides, hydroxamates, and heterocycles; sulfur nucleophiles for example thiols and thioamides; and carbon nucleophiles for example xcex2-ketoesters.
Aspects of the present invention have been realized by a process for preparing a heteroaromatic compound having a heteroaromatic nucleus substituted with one or more ether groups comprising the step of: condensing at least one hydroxy-group of a compound having the heteroaromatic nucleus, the at least one hydroxy group (xe2x80x94OH) being substituted at xcex1- or xcex2-positions with respect to a heteroatom of the heteroaromatic nucleus, with an alcohol containing one or more primary or secondary alcohol groups, optionally substituted with nitro, amide, ester, halogen, cyano or (hetero)aromatic groups using the redox couple of a triaryl- or trialkylphosphine and an azodioxo-compound at a temperature between xe2x88x9240xc2x0 C. and 160xc2x0 C. The heteroaromatic nucleus for the above-disclosed heteroaromatic compound and the above-disclosed compound are identical.
Further advantages and embodiments of the present invention will become apparent from the following description.
By a heteroaromatic nucleus is meant a heteroaromatic ring comprising carbon and non-carbon atoms with no substituents other than hydrogen atoms.
Substituted at the _xcex1-position relative to a heteroatom of a heteroaromatic nucleus means substituted at a carbon atom directly adjacent to a heteroatom of a heteroaromatic nucleus. There are two xcex1-positions relative to a heteroatom of a heteroaromatic nucleus either side of the heteroatom.
xcex2-position relative to a heteroatom of a heteroaromatic nucleus means substituted at a carbon atom directly adjacent to the xcex1-position relative to a heteroatom in a heteroaromatic nucleus. There are two xcex2-positions relative to a heteroatom of a heteroaromatic nucleus on the non-heteroatom side of each of the two xcex1-positions relative to a heteroatom in the heteroaromatic nucleus.
The Mitsunobu reaction is the condensation reaction of alcohols with an acidic compound (Hxe2x80x94Nu) using the redox couple of a triaryl- or trialkylphosphine and an azodioxo-compound in which the triaryl- or trialkylphosphine is oxidised to the corresponding phosphine oxide and the azodioxo-compound is reduced to the corresponding hydrazine, as described in Organic Reactions 1992, Vol. 42, 335-656 (Chapter 2 entitled xe2x80x9cThe Mitsunobu reactionxe2x80x9d by D. L. Hughes), and Organic Preparations and Procedures International, 1996, Vol. 28(2), 127-164 (xe2x80x9cProgress in the Mitsunobu Reaction. A Reviewxe2x80x9d by D. L. Hughes).
The term alkyl means all variants possible for each number of carbon atoms in the alkyl group i.e. for three carbon atoms: n-propyl and isopropyl; for four carbon atoms: n-butyl, isobutyl and t-butyl; for five carbon atoms: n-pentyl, 1,1-dimethyl-propyl, 2,2-dimethylpropyl and 2-methyl-butyl etc.
A chiral compound is a compound containing a chiral centre. A chiral centre is an atom, e.g. a carbon atom, that is attached to four different groups. A compound containing a chiral centre is not superimposable upon its mirror image and will exhibit chirality, chirality being the handedness of an asymmetric molecule. Such compounds, if isolated in a pure state, will generally exhibit rotation of polarized light detectable with a polarimeter.
Bu represents an n-butyl group.
Ph represents a phenyl group.
According to the present invention, a process for preparing a heteroaromatic compound having a heteroaromatic nucleus substituted with one or more ether groups comprising the step of: condensing at least one hydroxy-group of a compound having said heteroaromatic nucleus, said at least one hydroxy group (xe2x80x94OH) being substituted at xcex1- or xcex2-positions with respect to a heteroatom of said heteroaromatic nucleus, with an alcohol containing one or more primary or secondary alcohol groups, optionally substituted with nitro, amide, ester, halogen, cyano or (hetero)aromatic groups, using the redox couple of a triaryl- or trialkylphosphine and an azodioxo-compound at a temperature between xe2x88x9240xc2x0 C. and 160xc2x0 C.
According to a first aspect of the process, according to the present invention, the compound has at least two hydroxy groups substituted at xcex1- or xcex2-positions with respect to a heteroatom of said heteroaromatic nucleus.
According to a second aspect of the process, according to the present invention, the condensation is carried out at a temperature between 20xc2x0 C. and 80xc2x0 C.
According to a third aspect of the process, according to the present invention, the heteroaromatic nucleus is selected from the group consisting of pyridine, thiazole, isoxazole, imidazole, pyrazole, 1,2,3-triazole, furan, thiophene, pyrrole, selenophene, pyrazine, pyridazine and pyrimidine.
According to a fourth aspect of the process, according to the present invention, the heteroaromatic nucleus of said compound is further substituted with a nitro, amide, ester, cyano, acyl, acyloxy, carbonate, alkyl, aryl, carbocyclic or heterocyclic group.
According to a fifth aspect of the process, according to the present invention, the heteroaromatic nucleus is annulated to a carbocyclic or a heterocyclic ring system.
According to a sixth aspect of the process, according to the present invention, the annulated heteroaromatic nucleus is selected from the group consisting of indole, isoindole, thianaphthene, benzimidazole, benzofuran, quinoline, isoquinoline, cinnoline and quinoxaline.
According to a seventh aspect of the process, according to the present invention, the alcohol is an optionally substituted diol represented by formula (I): 
wherein R10, R11, R12 and R13 independently represent hydrogen or alkyl, alkoxy or acyl groups optionally substituted with nitro, amide, ester, halogen, cyano or (hetero)aromatic groups.
According to an eighth aspect of the process, according to the present invention, the alcohol is an optionally substituted diol represented by formula (II): 
where R14, R15, R16, R17, R18 and R19 independently represent hydrogen or alkyl, alkoxy or acyl groups optionally substituted with nitro, amide, ester, halogen, cyano or (hetero)aromatic groups. Optionally substituted 1,4-diols and 1,5-diols can also be used.
According to an ninth aspect of the process, according to the present invention, the alcohol is selected from the group consisting of 1,2-ethanediol (ethylene glycol), 2,3-butanediol, 1,2-butanediol, 1,3-propanediol, 2,2-dimethyl-1,3-propanediol, 2,2-diethyl-1,3-propanediol, 2,2-di-n-propyl-1,3-propanediol, 2,2-di-n-butyl-1,3-propanediol, 2,2-bis(bromomethyl)-1,3-propanediol, 3,3-bis(hydroxymethyl)-pentane, 2,2-bis(hydroxymethyl)-propane, 1,4-butanediol, 5,5-bis(hydroxymethyl)-nonane, 3,3-bis(hydroxymethyl)-heptane, 2,4-pentanediol and 1,2-dodecanediol.
Examples of suitable alcohols are methanol, ethanol and higher homologues optionally substituted with nitro, amide, ester, cyano or (hetero)aromatic groups, polyols, optionally substituted with nitro, amide, ester, halogen, cyano or (hetero)aromatic groups, such as glycol and other diols, glycerol and other triols, and derivatives with more than three alcohol groups.
According to a tenth aspect of the process, according to the present invention, the heteroaromatic compound having a heteroaromatic nucleus substituted with one or more ether groups is represented by the formula (III): 
where R20, R21, R22 and R23 independently represent unsaturated or saturated substituents such as alkyl or alkoxy groups optionally substituted with nitro, amine, amide, ester, cyano or (hetero)aromatic groups or R20 together with R21 or R21 together with R22, or R22 together with R23 represent the atoms necessary to complete an aromatic, heteroaromatic, heterocyclic or carbocyclic ring system with the proviso that at least one of R20, R21, R22 and R23 is an optionally substituted alkoxy group, and X is S, O or Nxe2x80x94R24, where R24 is an optionally substituted acyl or alkyl group e.g. a benzoyl or benzyl group.
According to an eleventh aspect of the process, according to the present invention, the heteroaromatic compound having a heteroaromatic nucleus substituted with one or more ether groups is represented by formula (IV): 
wherein R25 and R26 independently represent optionally substituted alkyl, alkoxy, carboxy or cycloalkyl substituents or R25 and R26 jointly represent the atoms necessary to form a heterocyclic ring, R27 and R28 represent CO2R29 substituents with R29 being an alkyl group e.g. methyl, ethyl, propyl or butyl and Y being S or Nxe2x80x94R30 where R30 is an optionally substituted acyl or alkyl group e.g. a benzoyl or benzyl group.
According to a twelfth aspect of the process, according to the present invention, the heteroaromatic compound having a heteroaromatic nucleus substituted with one or more ether groups is a 3,4-ethylenedioxythiophene or a 3,4-ethylenedioxypyrrole represented by formula (V): 
wherein R31 and R32 independently represent optionally substituted alkyl, alkoxy, carboxy or cycloalkyl substituents, R33 and R34 independently represent unsaturated or saturated substituents such as alkyl or alkoxy groups optionally substituted with nitro, amide, ester, cyano or (hetero)aromatic groups, and Z1 is S or Nxe2x80x94R35 where R35 is an optionally substituted acyl or alkyl group e.g. a benzoyl or benzyl group.
According to a thirteenth aspect of the process, according to the present invention, the heteroaromatic compound having a heteroaromatic nucleus substituted with one or more ether groups is a 3,4-propylenedioxythiophene or a 3,4-propylenedioxypyrrole represented by formula (VI): 
wherein R36 and R37 independently represent optionally substituted alkyl, alkoxy, carboxy or cycloalkyl substituents, R38, R39 and R40 independently represent unsaturated or saturated substituents such as alkyl or alkoxy groups optionally substituted with nitro, amide, ester, cyano or (hetero)aromatic groups, and Z2 is S or Nxe2x80x94R41 where R41 is an optionally substituted acyl or alkyl group e.g. a benzoyl or a benzyl group.
Larger ring systems (e.g. butylenedioxy systems) can also be prepared via this route.
Polyols react with heteroaromatic nuclei substituted with at least two hydroxy (xe2x80x94OH) substituents at xcex1- or xcex2-positions with respect to a heteroatom of the heteroaromatic nucleus to form alkylenedioxy-bridges between adjacent or non-adjacent carbon atoms of the heteroaromatic nucleus.
According to a fourteenth aspect of the process, according to the present invention, the heteroaromatic compound having a heteroaromatic, e.g. thiophene or pyrrole, nucleus substituted with one or more ether groups is chiral. This will depend upon the substitution pattern.
While it was found that the Mitsunobu reaction was somewhat sensitive to the degree of steric congestion of the alcohol employed (in fact tertiary alcohols do not react), the route is generally applicable to the synthesis of a host of dioxane ring functionalized thiophene.
The theoretical minimum molar ratio of azodicarboxylate to phosphine is 1. A ratio of up to 1.5 can be used, a molar ratio of 1.2 being found to be generally beneficial.
According to a fifteenth aspect of the process, according to the present invention, the molar ratio of azodioxo-compound to triaryl- or trialkylphosphine is 1.0 to 1.2.
The theoretical minimum ratio of azodioxo-compound or phosphine per hydroxy group is 1.0, with 1.25 being overkill.
According to a sixteenth aspect of the process, according to the present invention, the molar ratio of azodioxo-compound per hydroxy group is 1 to 1.2.
In a typical procedure, diethyl azodicarboxylate (2.4 equiv.) was dropwise added to a solution of 3,4-dihydroxy-thiophene-2,5-dicarboxylic acid diethyl ester (1.0 equiv.), diol (1.0 equiv.), and tributylphosphine (2.0 equiv.) in dry THF under argon at 25xc2x0 C. The reaction mixture was stirred for 1 h and stirred at reflux for 4-24 h. The reaction was cooled and THF was removed by a rotary evaporator. The residue was diluted with ether and stood for crystallization of tributylphosphine oxide for 12 h. Tributylphosphine oxide was filtered off and the filtrate was concentrated. Purification of the residue by chromatography on silica gel using hexane/ethyl acetate as an eluent afforded the desired product.
Suitable solvents for use in the process, according to the present invention, include tetrahydrofuran, dioxane, dichloromethane, chloroform, diethyl ether, dimethylformamide, toluene, benzene and hexamethylphosphoramide.
According to a seventeenth aspect of the process, according to the present invention, the azodioxo-compound is selected from the group consisting of diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1xe2x80x2-(azodicarbonyl)dipiperidine and N,N,Nxe2x80x2,Nxe2x80x2-tetramethylazodicarboxamide, as well as diazo derivatives mentioned in the following literature references: Organic Reactions 1992, Vol. 42, 335-656 (Chapter 2 entitled xe2x80x9cThe Mitsunobu reactionxe2x80x9d by D. L. Hughes), and Organic Preparations and Procedures International, 1996, Vol. 28(2), 127-164 (xe2x80x9cProgress in the Mitsunobu Reaction. A Reviewxe2x80x9d by D. L. Hughes) herein incorporated by reference.
Suitable azodicarboxylate ingredients, according to the present invention, are:
According to an eighteenth aspect of the process, according to the present invention, the triaryl- or trialkyl-phosphine is selected from the group consisting of triphenylphosphine, tri-n-butylphosphine, tris(dimethylamino)phosphine, (4-dimethylamino)-diphenylphosphine, diphenyl(2-pyridyl)phosphine as well as phosphine derivatives mentioned in the following references:
Organic Reactions 1992, Vol. 42, 335-656 (Chapter 2 entitled xe2x80x9cThe Mitsunobu reactionxe2x80x9d by D. L. Hughes), and Organic Preparations and Procedures International, 1996, Vol. 28(2), 127-164 (xe2x80x9cProgress in the Mitsunobu Reaction. A Reviewxe2x80x9d by D. L. Hughes) herein incorporated by reference.
Suitable phosphine ingredients, according to the present invention, are: